Dense genotyping of immune-related loci identifies HLA variants associated with increased risk of collagenous colitis.Karolinska Institutet, Stockholm, Sweden.
Karolinska Institutet, Stockholm, Sweden.
Karolinska Institutet, Stockholm, Sweden.
Christian-Albrechts-University of Kiel, Kiel, Germany.
Christian-Albrechts-University of Kiel, Kiel, Germany.
Karolinska Institutet, Stockholm, Sweden.
Karolinska Institutet, Stockholm, Sweden.
Karolinska Institutet, Stockholm, Sweden.
Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
Karolinska University Hospital, Stockholm, Sweden.
Karolinska University Hospital, Stockholm, Sweden.
Karolinska Institutet, Stockholm, Sweden.
Karolinska Institutet, Stockholm, Sweden.
arolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
Internal Medicine Center Eppendorf, Hamburg, Germany.
Siloah Hospital, Hannover, Germany.
Skåne University Hospital, Lund University, Lund, Sweden.
Karolinska Institutet, Stockholm, Sweden Sophiahemmet Hospital, Stockholm, Sweden.
Karolinska Institutet, Stockholm, Sweden.
(Christian-Albrechts-University of Kiel, Kiel, Germany)
Karolinska Institutet, Stockholm, Sweden BioCruces Health Research Institute and IKERBASQUE, Basque Foundation for Science, Bilbao, Spain..
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2017 (English)In: Gut, ISSN 0017-5749, E-ISSN 1468-3288, Vol. 66, no 3, p. 421-428Article in journal (Refereed) Published
Abstract [en]
OBJECTIVE: Collagenous colitis (CC) is a major cause of chronic non-bloody diarrhoea, particularly in the elderly female population. The aetiology of CC is unknown, and still poor is the understanding of its pathogenesis. This possibly involves dysregulated inflammation and immune-mediated reactions in genetically predisposed individuals, but the contribution of genetic factors to CC is underinvestigated. We systematically tested immune-related genes known to impact the risk of several autoimmune diseases for their potential CC-predisposing role.
DESIGN: Three independent cohorts of histologically confirmed CC cases (N=314) and controls (N=4299) from Sweden and Germany were included in a 2-step association analysis. Immunochip and targeted single nucleotide polymorphism (SNP) genotype data were produced, respectively, for discovery and replication purposes. Classical human leucocyte antigen (HLA) variants at 2-digit and 4-digit resolution were obtained via imputation from single marker genotypes. SNPs and HLA variants passing quality control filters were tested for association with CC with logistic regression adjusting for age, sex and country of origin.
RESULTS: Forty-two markers gave rise to genome-wide significant association signals, all contained within the HLA region on chromosome 6 (best p=4.2×10(-10) for SNP rs4143332). Among the HLA variants, most pronounced risk effects were observed for 8.1 haplotype alleles including DQ2.5, which was targeted and confirmed in the replication data set (p=2.3×10(-11); OR=2.06; 95% CI (1.67 to 2.55) in the combined analysis).
CONCLUSIONS: HLA genotype associates with CC, thus implicating HLA-related immune mechanisms in its pathogenesis.
Place, publisher, year, edition, pages
BMJ Publishing Group Ltd, 2017. Vol. 66, no 3, p. 421-428
Keywords [en]
COLLAGENOUS COLITIS; GENETICS; HLA GENES
National Category
Gastroenterology and Hepatology
Identifiers
URN: urn:nbn:se:liu:diva-125456DOI: 10.1136/gutjnl-2015-309934ISI: 000394495800007PubMedID: 26525574OAI: oai:DiVA.org:liu-125456DiVA, id: diva2:906389
Note
Funding agencies: Swedish Research Council [VR 2010-2976, VR 2013-3862]; Swedish Society of Medicine; Research Council of South-East Sweden (FORSS); County Council of Ostergotland (ALF); Bengt Ihres fond; Bengt Ihre Research Fellowship; Magtarmfonden; Stockholm County Coun
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